The present invention relates to improved methods for non-invasively determining a condition in the circulatory system of a subject. More particularly, the present invention is directed to non-invasively determining the functional cardiac output of the heart and the CO2 partial pressure of venous blood. With the method of the present invention, these conditions can be determined on a breath-by-breath basis. The present invention is also directed to determining changes in circulatory system conditions.
The physiological function of the heart is to circulate blood through the circulatory system to the body and lungs. For this purpose, the heart receives blood in atrial chambers during its relaxed or diastolic phase and discharges blood from its ventricle chambers during the contractile or systolic phase. The amount of blood discharged from a ventricle chamber of the heart per unit time is the cardiac output (CO). A typical cardiac output for the heart of a normal adult (at rest) is 5–6 liters per minute.
During circulation through the body, the blood is depleted of oxygen (O2) and is enriched with carbon dioxide (CO2) as a result of the metabolic activity of the body. A major purpose for blood circulation is to take venous blood that has been depleted in O2 and enriched in CO2 as a result of its passage through the tissues of the body and supply it to the lungs. In the alveoli of the lungs, O2 is supplied to the blood from the breathing gases, typically air, and CO2 is discharged into the breathing gases. The oxygenated arterial blood is then supplied to the body tissues. The gas exchange takes place in the capillaries of the lung because of the differences in concentration, or partial pressure, of O2 and CO2 in breathing gases, such as air, and in the venous blood. That is, the blood is low in O2 and high in CO2 whereas air is high in O2 and low in CO2.
To carry out the foregoing gas exchanges in the body and lungs of a subject, the heart is divided into a right side and a left side. The right side of the heart receives venous blood and pumps it to the lungs for oxygenation and CO2 reduction. The left side of the heart receives the oxygenated blood from the lungs and supplies it to the arteries of the body for circulation through the tissue of the body. The cardiac output of the right and left sides of the heart is generally equal.
The regulatory mechanisms of the body respond to variations in metabolic needs of body tissue by varying the cardiac output of the heart and the amount of gas exchange occurring in the lungs to maintain a sufficient supply of oxygen to body tissue and removal of CO2 from body tissue. The CO2 content of the blood is an indicator of the sufficiency of gas exchange occurring in the lungs. The gas exchange occurring in the lungs depends both on the amount of blood passing through the lungs, i.e. on the cardiac output (CO), and on the amount and efficiency of gas exchange occurring in the lungs. The amount of gas exchange can be grossly altered by changing the tidal volume of the lungs, as for example, by deep breathing. However, the amount of gas exchange, and particularly the efficiency of gas exchange, also depends on the physiological condition of the lungs.
A common condition reducing the gas exchange efficiency of the lungs is the presence of shunt perfusion or blood flow in the lungs. A shunt comprises pulmonary blood flow that does not engage in gas exchange with breathing gases, due to blockage or constriction in alveolar gas passages, or for other reasons. This shunt blood flow thus bypasses normal alveoli in which gas exchange is carried out. Upon leaving the lungs, the shunt blood flow mixes with the non-shunt blood flow. The former reduces the oxygen content and increases the CO2 content in the mixed arterial blood supplied to the body tissues.
It will be appreciated that only the non-shunt pulmonary blood flow through the lungs participates in the gas exchange function of the lungs and in oxygenation and CO2 removal in the blood of the subject. The quantity of blood that participates in such pulmonary gas exchange in the lungs is termed functional cardiac output (FCO). For diagnostic or other purposes, it is frequently desirable or essential to know this quantity.
While shunt conditions can occur in the lungs due to blockage brought about by disease, mechanical ventilation, particularly when the respiratory muscles of a subject are relaxed as during anesthesia, can result in an increase in the pulmonary shunt. The breathing gases supplied to the lungs can be enriched with oxygen under such conditions to assist in oxygenation of the blood. However, a sufficient amount of CO2 may not be removed from the blood when the pulmonary shunt is increased, giving rise to potentially adverse consequences to the subject.
The classic technique for determining the functional cardiac output of the heart is through use of the Fick equation
                              F          ⁢                                          ⁢          C          ⁢                                          ⁢          O                =                              V            ⁢                                                  ⁢            C            ⁢                                                  ⁢                          O              2                                                          C              ⁢                                                          ⁢              v              ⁢                                                          ⁢              C              ⁢                                                          ⁢                              O                2                                      -                          C              ⁢                                                          ⁢              c              ⁢                                                          ⁢              C              ⁢                                                          ⁢                              O                2                                                                        (        1        )            where,
VCO2in ml/min. is the amount of CO2 released from theblood in the circulatory system of the subject,CvCO2is the mixed venous blood CO2 content, forexample in ml CO2/ml of blood, andCcCO2is the end capillary blood CO2 content, i.e. theCO2 content in the blood leaving the ventilatedlungs.
The Fick equation states that, knowing the amount of CO2 gas released from the blood in a unit of time (e.g. the rate of gas transfer as a volume/minute) and the concurrent gas transfer occurring per unit of blood (i.e. volume of gas/volume of blood), the blood flow through the lungs (i.e. FCO expressed in volume/minute) can be determined.
If a portion of the pulmonary blood flow of the subject is in shunt, this will decrease the amount of CO2 released from the blood and the computation of Equation (1) provides an indication of the resulting decrease in functional cardiac output. In computing functional cardiac output using the Fick equation, the quantity VCO2 can be determined non-invasively by subtracting the amount of CO2 of the inhaled breathing gases, for example air, from the amount of CO2 of the exhaled breathing gases, taking into account changes in the amount of CO2 stored in the lungs and the deadspace in the breathing organs of the subject, such as the trachea and bronchi. The amount of CO2 stored in the lungs can be computed from the alveolar CO2 gas concentration, as determined from an end tidal breathing gas measurement, and the end expiratory volume VEE of the lungs. The end capillary blood CO2 content (CcCO2) can be determined non-invasively, with a fair degree of accuracy, from a measurement of the concentration of CO2 in the breathing gases exhaled at the end of the expiration of a tidal breathing gas volume, i.e. the end tidal (ET) CO2 level. The venous blood CO2 content (CvCO2), is often determined invasively. An alternate non-invasive approach for the determination of the CvCO2 can be seen in U.S. Pat. No. 6,042,550 and WO 01/62148. In these approaches, exhaled CO2 enriched breathing gases are rebreathed by the subject in subsequent inhalations. As rebreathing of the exhaled breathings gases continues, breath-by-breath, the end tidal CO2 partial pressure (PETCO2) increases until the end capillary blood CO2 partial pressure (PcCO2) is reached. At this point, it is postulated that the end tidal CO2 partial pressure (PETCO2), the alveolar CO2 partial pressure (PACO2), the end capillary blood CO2 partial pressure (PcCO2), and the venous blood CO2 partial pressure (PvCO2) are all equal and that this partial pressure can be converted to the venous CO2 content (CvCO2) for use in the Fick equation.
The need for the determination of the venous blood CO2 content (CvCO2) is eliminated by the use of a differential form of the Fick equation which arises from the following circumstances. As a subject rebreathes exhaled breathing gases, the end tidal CO2 partial pressure (PETCO2) and thus the alveolar CO2 partial pressure (PACO2) and end capillary CO2 content increases. This reduces the venous blood-alveolar CO2 partial pressure differences and because this is the driving force for CO2 elimination in the lungs, CO2 elimination is also reduced. It has been shown that the ratio of the change in CO2 elimination to the change in the end capillary blood CO2 content is equal to the functional cardiac output. See Gedeon A., et al. Med. Biol. Eng. Comp. 18:411–418 (1980). It is set forth in equation form, as follows:
      F    ⁢                  ⁢    C    ⁢                  ⁢    O    =            Δ      ⁢                          ⁢      V      ⁢                          ⁢      C      ⁢                          ⁢              O        2                    Δ      ⁢                          ⁢      C      ⁢                          ⁢      c      ⁢                          ⁢      C      ⁢                          ⁢              O        2            which, in terms of measured quantities is expressed as
                              F          ⁢                                          ⁢          C          ⁢                                          ⁢          O                =                                            V              ⁢                                                          ⁢              C              ⁢                                                          ⁢                              O                2                N                                      -                          V              ⁢                                                          ⁢              C              ⁢                                                          ⁢                              O                2                R                                                                        C              ⁢                                                          ⁢              c              ⁢                                                          ⁢              C              ⁢                                                          ⁢                              O                2                R                                      -                          C              ⁢                                                          ⁢              c              ⁢                                                          ⁢              C              ⁢                                                          ⁢                              O                2                N                                                                        (        2        )            
In the differential form of the Fick equation, the superscript N indicates values obtained in “normal” breathing conditions. The superscript R indicates values obtained during a short term “reduction” in the CO2 partial pressure difference between that in the alveoli and that in the blood. This results in reduced CO2 transfer in the lungs.
In using the differential form of the Fick equation, a first set of values for VCO2 and CcCO2 are obtained, as in the manner described above, under normal breathing conditions. These are identified by the superscript N. Thereafter, the amount of CO2 in the breathing gases for the subject is increased. This maybe accomplished by a partial re-breathing of exhaled breathing gases. See U.S. Pat. No. 5,836,300 and published International Patent Appln. WO 98/26710 that employ valve mechanisms for this purpose. Or, this may be accomplished by injecting CO2 into the inhaled breathing gases as described in U.S. Pat. No. 4,608,995. Further possibilities for altering the alveolar CO2 content include varying lung ventilation. This may be accomplished by altering the tidal volume or the respiration rate. Single breath maneuvers such as a deep breath as presented by Mitchell R R in Int J Clin Mon Comp 5:53–64 (1988), inspiratory hold as presented in WO 99/25244, or expiratory hold, may also be used for the purpose.
The CO2 enrichment increases the concentration of CO2 in the alveoli in the lungs and reduces the CO2 partial pressure difference between that of the breathing gases in the lungs and that in the venous blood. As noted above, it is that CO2 partial pressure difference that drives the CO2 gas transfer from venous blood to the breathing gases in the alveoli of the lungs. The reduced CO2 partial pressure difference reduces CO2 gas transfer in the lung and causes an elevation of the CO2 content in the blood downstream of the lung, i.e. in the arterial blood of the subject. In the time interval before the blood with elevated CO2 content circulates through the body and returns to the lungs, the CO2 content of venous blood (CvCO2) entering the lungs can be taken to be the same for both the initial, normal breathing conditions (N) and the subsequent, reduced CO2 partial pressure difference conditions labeled by the superscript R. This similitude permits the factor CvCO2 to be dropped out of the Fick equation when expressed in the differential form as Equation 2 so that the cardiac output is determined by the ratio of the change in released CO2 amounts (VCO2) between the normal (N) and reduced (R) gas exchange conditions to the corresponding change in the end capillary blood CO2 content (CcCO2) in the normal and reduced (R) gas exchange conditions. The need to determine the venous blood CO2 content (CvCO2) from the subject is thus eliminated.
The foregoing approach is also advantageous with ventilated or anesthetized subjects since the alteration of the CO2 content of the breathing gases can be effected by altering the ventilation provided to the subject. In the case of a subject anesthetized with a breathing circuit of the recirculating type, the alteration in CO2 content may be carried out by bypassing the CO2 absorber in the breathing circuit to increase the amount of CO2 in the breathing gases that are recirculated to the subject for inspiration.
While the above described techniques avoid the need to invasively determine venous blood CO2 content, other problems are created. Each time the cardiac output of the heart is measured, the CO2 content of the blood is increased. This is particularly true in procedures in which the subject rebreathes only exhaled breathing gases, i.e. “total rebreathing” since there is a corresponding blockage of CO2 removal or “washout” from the lungs of the subject. If the gas exchange capability of the subject's lungs is impaired, this exacerbates the problem of removing adequate amounts of CO2 from the blood of the subject, particularly if the measurements are carried out frequently. A period of time is required for CO2 levels in the venous and arterial blood of the subject to return to normal levels. This limits and prolongs the intervals between which functional cardiac output measurements can be taken.
Also, in cases in which a subject is being provided with a fixed volume of breathing gases, an increase in inspired CO2 volume is accompanied by a decreased volume of inspired oxygen. This may produce an undesired reduction in the oxygen content in the blood or require increased oxygen concentrations in the inspired breathing gases, following a cardiac output measurement, to restore oxygen levels in the blood to desired values.
The problem of limits in rapidity with which measurement can be taken may be overcome by the technique described in published PCT application WO 00/42908. This document discloses a method for breath-by-breath determination of cardiac output and blood gas related parameters. The method is based on simultaneous measurements of oxygen and carbon dioxide quantities and the breathing gas flow. From these measurements, the instantaneous respiratory quotient (RQ) is calculated as well as the respiratory quotient integrated for a whole expiration made by the subject. The respiratory quotient (RQ) of the subject is the volume of CO2 exhaled by the subject divided by the volume of O2 inhaled by the subject. The expired CO2 concentration at the moment the instantaneous respiratory quotient (RQ) has the value of 0.32 is then interpreted as the venous blood CO2 partial pressure (PvCO2). When the instantaneous respiratory quotient (RQ) equals the average respiratory quotient (RQ) for the whole expiration, the CO2 concentration is identified as the arterial blood CO2 partial pressure (PaCO2). The CO2 partial pressures thus obtained are then converted to blood gas content. Putting these blood gas contents and the amount of CO2 released from the blood (VCO2) in the non-differential form of the Fick equation, Equation 1, gives the functional cardiac output.
A shortcoming of this approach is that the measurement is based on respiratory quotients (RQ) experientially obtained from a group of subjects. Also, mean respiratory quotient (RQ) characteristics are not constant and may vary depending a number of circumstances, including diet. When a subject is ventilated, further variations even beyond usual limits transiently occur for up to an hour period when ventilation to the subject is changed.
Determination of the functional cardiac output through use of the Fick equations provides significant information regarding the amount of gas exchange occurring in the lungs of the subject. In addition to this information, it is often also desired to relate lung gas exchange amounts and blood gas properties to the metabolic needs of the subject's body. If, for example, the gas exchange occurring in the lungs is insufficient as compared to the metabolic activity of the subject, CO2 will accumulate in the subject's blood and the CO2 content of the blood will rise. Clinicians may therefore wish to look at the levels of CO2 and other gases in the blood of a subject. Thus, while the differential form of the Fick equation is designed to eliminate the need to measure CO2 levels in venous blood when determining functional cardiac output, there may still exist a need for this information for other medical purposes.
Historically, CO2 levels in venous blood have been obtained by invasively removing a blood sample from the subject and using a blood gas analyzer to analyze the gaseous properties of the blood sample. A blood gas analyzer typically expresses these properties as the partial pressures of the various gases in the blood. The use of partial pressures is based on Dalton's law which states that in a mixture of gases, such as O2, N2, CO02, etc., in a container or in a medium, such as blood, the pressure exerted by each gas, i.e. its partial pressure, is the same as that which the gas would exert if it alone occupied the container or medium. This allows the partial pressure of a gas to serve as an expression of gas quantity. Physicians, and other clinicians, have become accustomed to seeing and working with blood gas properties expressed as partial pressures rather than as gas content expressed volumetrically or otherwise. Thus, while determination of functional cardiac output requires blood gas content, in many other instances it is desired to express blood gas properties as partial pressures. That is, an arterial CO2 blood quantity could be expressed as a partial pressure, for example, PaCO2, rather than as a content, CaCO2, or a venous property could be expressed as a partial pressure as, PvCO2, rather than as a content, CvCO2.
However, in relating blood CO2 contents and blood CO2 partial pressures, there is often a failure to recognize that the levels of different gases in the blood are interrelated. Thus, the higher the O2 level in the blood, the lower the capacity of the blood to transport CO2. Stated in a different way, if the amount of CO2 in the blood is to remain constant as the O2 content of the blood changes, for example, increases, the CO2 partial pressure must also change, i.e. also increase. This phenomenon is known as the Halldane effect and failure to take this effect into account will affect the accuracy by which, for example, the CO2 partial pressure of venous blood (PvCO2) can be determined from CO2 blood content measurements obtained from the subject.
A common shortcoming of discrete measurements of circulatory system conditions of the above type is the ignorance of a value, such as functional cardiac output, between the measurements. Cardiac output or functional cardiac output remain unchanged as long as both the CO2 elimination and the venous to arterial (or end-capillary) CO2 content difference remain unchanged. The CO2 elimination and the end-tidal CO2 fraction from which the CcCO2 can be determined can be measured on breath-by-breath basis, but the changes in CvCO2 for use in Fick Equation 1 remain undetected.
An approach to dealing with this shortcoming is noted in U.S. Pat. No. 6,238,351, which discloses a method to compensate the venous to arterial CO2 content difference for changes that can be detected. These changes include changes in ventilation, CO2 elimination, end-tidal CO2, and time. However, a problem with such a method is to determine the degree of compensation needed when a change is detected in one or more of the detected parameters.